Le cancer du sein triplement négatif.

As you can read in one of a series of UCSF.edu articles on promising approaches to defeating breast cancer, the trio’s game plan calls for targeting an inflammatory response that helps fuel triple-negative breast cancer growth, and to help carry it out they are equipped with a new $6.5 million grant from Susan G. Komen for the Cure.

Not all breast cancers are the same when it comes to the genetic makeup of their tumor cells, and the triple-negative variety has nasty stuff. What it doesn’t have is a reliance on genes that other types of breast cancers often depend on — the estrogen receptor, the progesterone receptor, and a third receptor called HER2. Hence the name triple negative.

After years of research, genetic profiling, and drug development, oncologists now have treatments designed to target two of these receptors in breast cancers that have them. Raloxifene and tamoxifen target the estrogen receptor, while Herceptin targets HER2. Oncologists often use these treatments along with other therapies to help knock those cancers out of the park for good, and compared to decades past, they have a high batting average. Overall, more than nine out of ten women diagnosed with breast cancer now survive five years or more.

However, for the roughly one in six women with breast cancer who have triple-negative breast cancer, the odds are worse. About three out of four survive five years or more. The tumors sometimes grow aggressively — from an undetectable to a difficult-to-treat stage between regular screening mammography exams, for instance. A new study finds that triple-negative tumors are more rapidly deadly than other breast cancers when they spread to the brain.

Fortunately, medical researchers are making new genetic discoveries about triple-negative breast cancer that may translate directly into better treatment. For one thing, there may be genetic subtypes within this often deadly tumor type, maybe even some that will be susceptible to already existing drugs used in new combinations. But for UCSF researchers a fruitful line of research centers on a different cell type — immune cells called macrophages, which aid and abet triple-negative breast cancers.

Better treatments for triple-negative breast cancer would also help reduce racial disparities in cancer treatment outcome. Triple-negative breast cancer accounts for a disproportionately higher share of breast cancers that occur among Hispanic and African American women. Tragically, these deadly tumors also disproportionately affect younger women, with even more years of life lost.

The team is headed by UCSF laboratory scientist Lisa Coussens, PhD, UCSF oncologist Hope Rugo, MD, and Shelley Hwang, MD, a surgical oncologist at Duke University. The researchers' preliminary findings are promising. “Data from our lab show that tumor-bearing mice treated with a drug that reduces infiltration of macrophages into tumors, PLX3397, enhances sensitivity to chemotherapy, thereby reducing the spread of cancer to the lungs and prolonging survival,” they report. They plan to do additional studies in animals before testing the drug in women.

While it is already known that breast cancer cells create the conditions for their own survival by communicating their needs to the healthy cells that surround them, Australian researchers have identified a new way of turning off that cellular cross talk.

Clinical Associate Professor Sandra O’Toole and Dr Alex Swarbrick, from Sydney’s Garvan Institute of Medical Research, analysed breast tumour samples from a cohort of 279 women with advanced breast cancer, revealing that the higher the level of hedgehog, the more aggressive the cancer.

Le plus il y a de hedgegog, le plus le cancer est agressif.

Having discovered high levels of hedgehog in some breast cancer patients, they went on to over-produce the protein in mouse models of basal breast cancer. Mice developed tumours that grew and spread through the body rapidly. When hedgehog was blocked, the tumour growth and spread were significantly slowed.

“Finding an effective drug target for basal breast cancer is a very high priority. It is often referred to as ‘triple negative disease’, because it doesn’t produce any of the oestrogen, progesterone or HER2 receptors, targets of the drugs tamoxifen and Herceptin, which are very effective in other breast cancers.”

A/Prof O’Toole, also a pathologist at Sydney’s Royal Prince Alfred Hospital, undertook the study as part of her PhD. “These findings may provide some hope to the many women who succumb to breast cancer each year, especially the basal sub-type, although obviously it is early days,” she said.

“More work in animal models is needed to understand exactly how best to block this pathway.”

Saranya Chumsri, M.D., an oncologist at the Greenebaum Cancer Center and assistant professor of medicine at the University of Maryland School of Medicine, is the principal investigator of the newly opened National Cancer Institute-funded study. The trial is based on laboratory studies by Angela H. Brodie, Ph.D., an internationally recognized University of Maryland breast cancer researcher, and her colleagues. Their research, recently published in the journal Cancer Research, found that entinostat can cause triple-negative breast cancer cells to become sensitive to a hormone therapy such as an aromatase inhibitor. Dr. Brodie pioneered the development of aromatase inhibitors, a class of breast cancer drugs that reduces the level of estrogen produced by the body, thereby cutting off the fuel to cancer cells.

In this Phase II trial, doctors will treat newly diagnosed postmenopausal patients with entinostat and an aromatase inhibitor called anastrozole (Arimidex) before they have surgery to remove their cancer. Researchers will analyze tissue from the tumor and blood samples to evaluate whether the treatment is effective. After surgery, patients will receive standard treatment, such as chemotherapy and radiation.

"We hope that entinostat will make the tumor cells more sensitive to the drug anastrozole, causing the tumor to shrink or, at the very least, stop growing," Dr. Chumsri says. "For patients with triple-negative breast cancer, chemotherapy is currently the only drug treatment option, and it has a lot of side effects compared to hormone therapies like anastrozole."

Triple-negative breast cancer is unique in that it lacks three common receptors in the cell -- estrogen, progesterone or human epidermal growth factor 2 (HER2), which are the targets of drugs widely used today to treat breast cancer. As a result, this cancer can be very difficult to treat; it doesn't respond to therapies that target estrogen and progesterone receptors, such as tamoxifen (Nolvadex), fulvestrant (Faslodex) and aromatase inhibitors (Femara, Arimidex and Aromasin), or to HER2-targeted therapies such as trastuzumab (Herceptin) and lapatinib (Tykerb).

About 15 to 20 percent of breast cancers are triple-negative. For unknown reasons, there is a higher prevalence of this type of breast cancer among African-Americans, young women and women with the BRCA1 gene mutation. African-American women are twice as likely as white women to have this type of cancer, which can be very aggressive and spread to other parts of the body, such as the lungs, liver and brain.

The clinical trial is based on laboratory studies by Dr. Brodie, a professor of pharmacology and experimental therapeutics, and Gauri J. Sabnis, Ph.D., an assistant professor of pharmacology and experimental therapeutics, at the University of Maryland School of Medicine, in collaboration with Saraswati Sukumar, M.S., Ph.D., a professor of oncology and pathology at the Johns Hopkins University School of Medicine. Their research showed that entinostat can sensitize triple-negative breast cancer cells to treatment with an aromatase inhibitor, and when combined with an aromatase inhibitor, also reduce the growth and spread of tumors in animal models.

"Adding to her long list of remarkable achievements, Dr. Brodie has continued her research into aromatase inhibitors, searching for ways to overcome tumors' resistance to treatment," says E. Albert Reece, M.D., Ph.D., M.B.A., vice president of medical affairs at the University of Maryland and dean of the University of Maryland School of Medicine. "This multicenter clinical trial led by Dr. Saranya Chumsri is an excellent example of how our scientists turn discoveries made in the lab into new treatments that may benefit patients."

Entinostat is an oral, selective histone deacetylase (HDAC) inhibitor. This anti-cancer agent is being developed by Syndax Pharmaceuticals, Inc., and is being investigated in other clinical studies for the treatment of advanced estrogen receptor-positive breast cancer, advanced non-small-cell lung cancer, advanced colorectal cancer and Hodgkin's lymphoma.

Triple-negative breast cancer patients in this clinical trial will take entinostat weekly and anastrozole once daily for two to four weeks while they are waiting to have surgery. Researchers will use blood tests and tissue analysis of tumors to evaluate the effectiveness of the combination therapy.

Researchers hope to enroll a total of 41 patients at 20 sites, including the University of Maryland Greenebaum Cancer Center. The centers involved in the study are affiliated with the University of Chicago Phase II study research consortium and the California Cancer Consortium.

Dr. Chumsri says that if the results of this trial are positive, researchers plan to launch a larger study to test the combination therapy on women whose cancer has metastasized to other parts of the body. "These women have limited treatment options. Hopefully, this treatment would give them a longer period in which their cancer is not progressing, with only minimal side effects compared to chemotherapy," she says.

Kornelia Polyak, MD, PhD, a breast cancer geneticist at Dana-Farber, and colleagues found that a large proportion of cells within these tumors showed elevated activity in a network of genes called the Jak2/Stat3 pathway. Experiments have demonstrated that a drug specifically aimed to block this pathway halted the growth of such tumors in mice. The report will be published online June 1 by The Journal of Clinical Investigation in advance of its July print issue.

Polyak called the strategy very promising. "The discovery of these targets will rapidly lead to clinical trials with the hope of achieving one of the first specific therapies for triple-negative breast cancers," said Polyak, senior author of the findings that was submitted by a large collaboration of scientists.

Jak2/Stat3 inhibitors are already in advanced phases of clinical testing for certain blood cancers that are driven by the Jak2/Stat3 pathway. Polyak noted that because these inhibitors have already been tested in humans and appear to be relatively non-toxic, it should be possible to begin testing them in breast cancer patients soon.

Triple-negative breast cancers are characterized by a lack of estrogen, progesterone, and HER2 receptors, which makes them unresponsive to targeted treatments that block those receptors. These tumors, also termed "basal-like," make up an estimated 15 to 20 percent of breast cancers and tend to occur in younger women, those with BRCA1 gene mutations, and black women.

Polyak previously found that triple-negative tumors typically contain a large number of "stem-like" breast cancer cells, labeled CD44+CD24- cells, referring to identifying markers on their surfaces. They resemble stem cells, as they constantly renew themselves and make tumors likely to spread to distant organs.

As a result, Polyak and colleagues believe that new treatments aimed at specifically knocking out these CD44+CD24- cells with activated Jak2/Stat3 signaling could be useful in combating triple-negative cancers and potentially other tumors that contain these cells.

The investigators surveyed genes present in CD44+CD24- cells and found 1,576 genes that differed from those in other, more differentiated epithelial cancer cells within tumors. Additional experiments assessing the viability of CD44+CD24- cells when each of these genes was inhibited individually narrowed the field to 15 genes that were required for their growth and thus looked like promising targets for selective drugs. These 15 genes were linked to the overactive Jak2/Stat3 pathway, which in turn was triggered by a growth factor signal, interleukin-6, or IL-6.

When the activity of several of those genes was blocked in CD44+/CD24- tumor cells, the level of Stat3 signaling was reduced and cell growth was suppressed, the researchers said.

Polyak said that inhibitor drugs exist for five of the genes identified in the CD44+CD24- cell network, and two of those drugs are currently in advanced clinical testing.

Nancy Lin, MD, a Dana-Farber oncologist who will lead the clinical trial of a Jak2/Stat3 inhibitor in breast cancer patients, said women who volunteer for the trial will be tested to determine whether the pathway is abnormally activated in their cancer. Those who test positive will be candidates for treatment with the drug. According to Lin, the abnormal pathway is expected to be found in 50 to 60 percent of patients with triple-negative cancers.

First author of the report is Lauren Marotta, PhD, a graduate student in the Polyak laboratory. The other authors are from Dana-Farber, Harvard Medical School, Brigham and Women's Hospital, the Harvard School of Public Health, the Broad Institute of MIT and Harvard, Memorial Sloan-Kettering Cancer Center, and GeneGo, Inc., as well as institutions in Spain, Russia, and Korea.

The research was supported in part by Novartis, a National Cancer Institute SPORE grant, the Breast Cancer Research Foundation, and the American Cancer Society.

The leptin receptor antagonist peptide, developed by researchers Laszlo Otvos and Eva Surmacz, could become an attractive option for triple negative breast cancer treatment, especially in the obese patient population. The researchers published their findings online in the European Journal of Cancer.

According to the researchers, triple-negative breast cancers -- which represent 10-20 percent of all mammary tumors -- are characterized by the aggressive traits that is often found in younger women and have been associated with poor prognosis.

"Obesity increases the risk for triple-negative breast cancer development," said Surmacz, an associate research professor in biology at Temple. "Because triple-negative breast cancer patients are unresponsive to current targeted therapies and other treatment options are only partially effective, new pharmacological modalities are urgently needed."

Leptin, a protein that is always elevated in obese individuals and is higher in women than in men, can act locally within the body and promote cancer development by inducing the survival and growth of tumor cells, counteracting the effects of cancer therapies, and promoting metastasis. Previous studies by Surmacz suggested that leptin levels are significantly higher in aggressive breast tumors than in normal breast tissue.

In their study, the researchers examined if the leptin receptor was a viable target for the treatment of this type of cancer. It has been shown that in human triple negative breast cancer tissues, the leptin receptor was expressed in 92 percent and leptin in 86 percent of cases.

Using a mouse model of triple negative breast cancer, they tested the new leptin receptor antagonist peptide and compared it to conventional chemotherapy. The leptin receptor antagonist peptide extended the average survival time by 80 percent, compared to 21 percent for chemotherapy. The peptide was found to be non-toxic even up to the highest dose administered, said Sumacz.

"If this peptide, with its advantageous administration route and safety profile, can be developed as a drug it could be a useful addition to the existing oncology drug repertoire against various forms of cancer, including breast, brain, prostate and colon cancers," said Sumacz.

The early promise of treating triple-negative and basal-cell breast cancers with poly (ADP-ribose) polymerase (PARP) inhibitors is yet to be realized, according to Lisa A. Carey, M.D., who will be delivering a presentation on treatment options for these patients at the Miami Breast Cancer Conference this week.

Carey, an Associate Professor of Medicine and Medical Director of the UNC Breast Center Lineberger Cancer Center at the University of North Carolina, spoke with cancernetwork.com from her office in Chapel Hill, and shared her thoughts on the challenges of treating triple-negative and basal-cell breast cancers.

“The first thing we have to recognize is that triple-negative and basal-like breast cancers aren't the same thing. 'Triple negative' is really a term of convenience, meaning patients who do not have a hormone receptors or HER2 expression in their tumor. The basal-like molecular subtype of breast cancer makes up the majority, but not all of them. So, we do have to recognize that we use 'triple negative' as kind of a surrogate for the biology of basal-like breast cancer. We're always misclassifying some of these tumors in ways that might, in the future, become quite important.

“That said, regardless of how you examine these tumors, triple negative or basal-like, there are clearly prognostically different sub-groups within them. The easiest way to sort that out is to look at simple clinical variables. We know that a small node, triple-negative breast cancer has a far better prognosis than a much larger nodally-involved tumor. So there are things beyond just the triple-negative status that are very important in establishing prognosis.”

“The studies on PARP inhibitors have kind of fallen into two categories. There are a number of PARP inhibitor studies that have included BRCA mutation carriers, so BRCA1 or BRCA2 mutation carriers—women who have a familial form. In fact, these studies with drugs like Olaparib (AstraZeneca) or Veliparib (Abbot Laboratories), are small but they are fairly consistent in suggesting a role for these drugs—both of which are oral PARP inhibitors—in treating familial breast cancer and, for that matter, familial ovarian cancer, also; which fits really fits very strongly with the pre-clinical rationale for how these drugs work.

“So, people who have an inherited aberrancy in their DNA damage-response pathways should be sensitive to drugs that kind of kick out the other leg that the DNA damage-response is standing on. Now, when we get to triple negative, it's become a much more complicated story.

“There have been a number of pre-clincial studies that suggested that basal-like breast cancer, that molecular subtype that makes up most triple negatives, has elements and characteristics that are very reminiscent of BRCA1-associated breast cancer. In fact, when BRCA1 mutation carriers—women who carry one of these abnormal genes from birth—get breast cancer, they almost always get basal-like breast cancer.

“There was a study using a drug called Iniparib (BiPar Sciences, Sanofi Aventis), which is an IV drug with PARP activity. It is not totally clear if its mechanism of action is through that activity or through something else. Regardless, it was certainly initially thought of as being a PARP inhibitor. There was a Phase II randomized study with Iniparib that was published in the New England Journal of Medicine (2011; 364: 205-214) a couple months ago that showed what appeared to be very strong activity augmenting outcomes in patients treated with chemotherapy if you added this Iniparib to the chemotherapy.

“That story got more complicated because of two things. The studies with both Olaparib and Veliparib that have been done in triple negatives that don't have a familial component are small but have not, so far, shown us a great way forward in terms of this being a very effective strategy. We don't really know because they are very small and immature and Olaparib has been pulled from breast cancer development, so we won't be seeing any more data any time soon. But, they were not the kind of exciting data that we'd seen in mutation carriers.

“Separately, there was a Phase III study, the registration study, for Iniparib—which used to be called BSI 201—really hard on the heels of publication of the Phase II study. The first report of the Phase III came out as a press release that suggested that even though progression-free survival and overall survival were substantially and significantly improved in the Phase II setting this was not the case in the Phase III setting—for reasons that are entirely unclear at this point.

“The data have not, themselves, been released. I think the company is planning to present it at ASCO; if so, I think we'll have more to work with. But as of right now, the Phase III—which is, of course, the definitive study—did not replicate the Phase II. So, the role of Iniparib at this point is unclear.”

She will also be sharing the next steps beyond PARP inhibitors for treatment.

“For awhile, we've been looking in the direction of PARP inhibitors because of some of this early and exciting data. I think we're back to the drawing board, a little bit, for all the options for treating these subtypes of breast cancer.

“With basal-like breast cancer, and if you look at most triple negatives, there's a lot of heterogeneity. There may be so much heterogeneity in these tumors that it may be difficult to come up with a uniform approach using one or even a couple of drugs.

“The antiangiogenic strategies have shown some benefit in this group. The bevacizumab(Drug information on bevacizumab) (Avastin, Genetech) studies, if anything, have shown as much benefit, if not more, in this subset than anything else. EGFR (epidermal growth factor receptor) and other sorts of signaling pathway-directed studies have shown modest activity—not enough to take to the bank—but they show there is some role for targeting that particular pathway. And there are a number of people looking at things like PI3 kinase signaling pathway and things like that, which are the likely future treatment directions.

“In my opinion, chemo will remain a mainstay of the treatment of this subtype for a long time. The ability to target it further will likely depend on our being much more sophisticated in genomic studies about how to identify what the Achilles' heel of a particular tumor is before we decide on treatment.”

HOUSTON -- (March 21, 2011) -- Researchers led by Baylor College of Medicine have found a new way to tackle a difficult-to-treat form of breast cancer – a discovery that is being translated into human studies with currently approved FDA drugs.

The new strategy begins with their discovery that a gene called PTPN12 plays a pivotal role in triple negative breast cancer, an aggressive form of the disease that accounts for approximately 20 percent of new cases of the disease and is resistant to common drugs such as Tamoxifen and Herceptin®. Until now, the genes that drive the growth of triple negative breast cancer have been a mystery, making it difficult for scientists to devise new therapies for this disease.

In a report in a recent issue of the journal Cell, Dr. Thomas F. Westbrook of BCM and colleagues describe their new understanding of the forces that drive this aggressive disease and, more important, how to use a combination of drugs to block those forces.

"This study gives us promising new insight into how to treat patients with triple negative breast cancer and possibly other cancers," said Westbrook, assistant professor of biochemistry and molecular biology and molecular and human genetics at BCM and senior author of the report.

In this study, Westbrook and his collaborator, Dr. Stephen J. Elledge of Harvard Medical School, screened literally tens of thousands of genes for their role in human breast cancer. They found that the gene PTPN12 prevents or suppresses breast cancer. Next, together with researchers at the BCM Lester & Sue Smith Breast Center, Westbrook showed that most triple negative breast cancers have lost that protective gene.

Most important, the researchers found that the loss of PTPN12 unleashes a specific combination of cancer-promoting enzymes called tyrosine kinases. These enzymes work in concert to cause aggressive growth and spread of triple negative breast cancer. Blocking just one kinase is not enough, said Westbrook. Specific combinations of kinases have to be blocked to stop the growth of the breast cancer.

Because drugs that block some of these kinases are already FDA-approved for patients, this study provides an exciting strategy for combining specific kinase inhibitors to combat triple negative breast cancer as well as other forms of cancer.

"This discovery is an important advance for patients, because we may now be able to rationally combine drugs that inhibit these kinases to treat patients with triple negative breast cancer (and other cancers) that were previously thought intractable to such therapies," said Westbrook, also a member of the NCI-designated Dan L. Duncan Cancer Center.

Westbrook and colleagues showed that inhibiting specific combinations of these kinases effectively blocks the growth and spread of triple negative breast cancer in animals. Because drugs that block some of these kinases are already approved for patients, this study provides an exciting strategy for combining specific kinase inhibitors to combat triple negative breast cancer as well as other forms of cancer.

"But the strategy of which medicines to combine is difficult to predict. Here, we are providing a new rationale to combine a specific set of medicines to treat this debilitating disease, and we are now pursuing clinical trials to test this new idea."

In addition to triple negative breast cancer, PTPN12 may play a role in other difficult-to-treat malignancies such as lung cancer. In fact, there may be a whole class of genes that behave like PTPN12 to inhibit kinases and cancer formation.

It's a disease that does not typically respond to treatment with standard chemotherapy drugs and therefore, diagnosis can come with a poor prognosis. But a new study out of Massachusetts General Hospital Cancer Center in Boston indicates this type of disease is sensitive to the drug cisplatin.